The objective of this proposal is to achieve a better understanding of cytotoxic reactions that are mediated by normal human lymphocytes. In the phenomenon of antibody dependent cell-mediated cytotoxicity (ADCC) antibody sensitized cells are lysed by normal lymphocytes which have not been previously sensitized to the pertinent cell surface membrane antigens. Both IgM and IgG antibody, bound to a target cell, can induce ADCC, and in each case lymphocyte-target cell contact is required. This membrane-membrane contact apparently makes possible the interaction of Fc-receptors on the lymphocytes and the antibody Fc region on the target cell. This interaction can be blocked by the addition of unrelated antibody and antibody Fc fragments presumably by steric hindrance at the Fc receptor. However, under some conditions the addition of unrelated antibody-antigen complexes or antibody fragments enhances the cytotoxicity. This differential modulation is seen in the enhancement of IgM dependent ADCC by IgG antigen complexes and heat aggregated IgG. Furthermore, we have found that IgG-complexes and aggregates induce normal lymphocyte mediated lysis of nonsensitized sheep red blood cells (SRBC). We will further evaluate the membrane interactions that modulate the cytotoxic activity of normal lymphocytes. Lymphocytes will be fractionated by various means into subpopulations of B-cells, T cells and null cells to determine which cells are active in these reactions. The possibility that a lymphocyte can be armed in vivo with anti-SRBC IgM and mediate lysis of SRBC in vitro will be investigated. Attempts will be made to arm lymphocytes in vitro and in vivo with IgM of various specificities. We will conduct experiments to determine the basis for the apparent increase in IgM-ADCC induced by IgG aggregates or immune complexes. The possibility that cells can be armed in vivo with IgM and that IgM-ADCC requires lymphocyte interaction with an IgG antigen complex may be of importance in immune complex disease as well as cancer.